Non-invasive measurement of blood glucose by any method including optical spectroscopy techniques has remained an elusive target for at least two decades. Blood, tissue, and most excreted fluids contain numerous substances which confound glucose spectral signatures. On the other hand, aqueous humor (AH) filling the anterior chamber of the eye (between the lens and cornea) contains relatively few molecules capable of interfering with the spectroscopic detection of glucose. These are primarily lactate, ascorbate, and urea. This fact, and its optically accessible location behind the cornea, make AH an attractive choice as a site on which to attempt non-invasive analysis of glucose.
Pohjola (Acta Ophthalmologica Suppl. 88, 1-80 (1996)) showed that the ratio of aqueous glucose to plasma glucose in normal euglycemic individuals is related to age and ranges from 0.6 to 0.9. He further showed in seven humans with steady-state hyperglycemia that similar ratios applied. No data exists on the equilibration time of aqueous humor glucose with changes in plasma glucose in humans.
Numerous investigators over the years have suggested that the ratio of aqueous glucose to plasma glucose in the normoglycemic rabbit ranges from 0.42 to 1.01 (S. Pohjola, supra; D. Reddy and V. Kinsey, Arch. Ophthalmol. 63, 715-720 (1960); M. Reim et al., Ophthalmologica 154, 39-50 (1967); W. March et al., Diabetes Care 5, 259 (1982)). It is uncertain whether this variability is normal or could be attributed to differences in glucose measurement techniques, collection techniques, sample storage, and anesthesia. The relationship of aqueous glucose to rising, or falling, plasma glucose has not been previously studied in rabbits.
Cote has reviewed the relative strengths and weaknesses of optical glucose sensing techniques (J. Clin. Engineering 22, 253 (1997)). Raman spectroscopy is potentially attractive because it can distinguish glucose in water solutions containing various levels of other optically active metabolites (S. Wang et al., Applied Optics 32, 925 (1993)). Raman spectroscopy measures the shift in the wavelength of incident light as it is scattered by molecules. Any given molecule causes a characteristic shift in the spectrum of scattered light, which is dependent upon its intermolecular and intramolecular bonds. This is in contradistinction to fluorescence, which is caused by changes in electron energy states, and does not shift relative to the wavelength of incident light.
Wicksted et al, (Appl. Sectroscop. 49, 987 (1995)) suggest that the Raman signature for glucose can be identified in aqueous humor samples, and Goetz, et al (IEEE Trans. Biomed. Eng. 42, 728 (1995)), have demonstrated that higher than physiologic levels of glucose can be measured with Raman spectroscopy in water solutions. J. Lambert et al., (LEOS Newsletter 12, 19-22 (1998)) suggest that measurement of glucose at physiologic levels is possible in water solutions containing other analytes normally found in aqueous humor. When solutions containing fluorescent substances are studied, however, the fluorescence signal can overwhelm the relatively weak Raman-shifted signal. This is a potential problem if Raman spectroscopy is applied to aqueous humor, which contains proteins that fluoresce.
U.S. Pat. No. 5,243,983 to Tarr et al. suggest a non-invasive blood glucose measurement system using stimulated Raman spectroscopy. Stimulated Raman spectroscopy requires the use of both a pump and a probe laser beam. The probe laser beam is used to measure the stimulated Raman light at a single wavelength after transmission across the anterior chamber of the eye. This is undesirable, since an optical component contacting the eye is required to direct the beam across the anterior chamber. In addition, use of a single wavelength may limit the ability to measure glucose at physiologic levels within tissue containing many other Raman scattering chemicals.
U.S. Pat. No. 5,433,197 to Stark suggests a non-invasive glucose measurement apparatus that employs broad band infrared light stimulation.
U.S. Pat. No. 5,553,617 to Barkenhagen suggests a non-invasive method for measuring body chemistry from the eye of a subject by measuring a spectral response such as a Raman scattering response. While it is suggested that the invention may be used for medical applications such as the determination of sugar in diabetics, specific details on how this might be accurately carried out are not provided.
U.S. Pat. No. 5,710,30 to Essenpreis suggests a method for measuring the concentration of glucose in a biological sample such as the eye (see FIG. 4 therein) with interferometric measurement procedures.
U.S. Pat. No. 5,666,956 to Buchert et al. suggests that an instrument for the non-invasive measurement of a body analyte can be based on naturally emitted infrared radiation.
In spite of the foregoing efforts, a commercially viable, non-invasive, blood glucose monitor based on a non-invasive analysis of the aqueous humor of the eye has not yet been developed. Difficulties in developing such a device include correlation of aqueous humor glucose levels to blood glucose levels, the difficulty of obtaining accurate measurements, and the need to minimize damaging effects to the eye caused by excessive exposure to light in an instrument that will be used by subjects on a repeated basis. Accordingly, there is a continued need for new methods for the non-invasive analysis of blood glucose levels.